OBJECTIVE: Norpropoxyphene (NP) is a major metabolite of propoxyphene (P), a relatively weak mu-opioid receptor agonist. Toxic blood concentrations ranging from 3 to 180 mumol/l have been reported and the accumulation of NP in cardiac tissue leads to naloxone-insensitive cardiotoxicity. Since several lines of evidence suggest that not only block of INa but also IK block may contribute to the non-opioid cardiotoxic effects of P and NP, we investigated the effects of P and NP on HERG channels. HERG presumably encodes IKr, the rapidly-activating delayed rectifier K+ current, which is known to have an important role in initiating repolarization of action potentials in cardiac myocytes. METHODS: Using the 2-microelectrode voltage clamp technique we investigated the interaction of P and NP with HERG channels, expressed in Xenopus oocytes. RESULTS: Our experiments show that low drug concentrations (5 mumol/l) facilitate HERG currents, while higher drug concentrations block HERG currents (IC50-values of approx. 40 mumol/l) and dramatically shift the reversal potential to a more positive value because of a 30-fold increased Na(+)-permeability. P and NP also alter gating of HERG channels by slowing down channel activation and accelerating channel deactivation kinetics. The mutant S631C nullifies the effect of P and NP on the channel's K(+)-selectivity. CONCLUSION: P and NP show a complex and unique drug-channel interaction, which includes altering ion-selectivity and gating. Site-directed mutagenesis suggests that an interaction with S631 contributes to the drug-induced disruption of K(+)-selectivity. No specific role of the minK subunit in the HERG block mechanism could be determined.